Scofield was trained as an actor at the Croydon Repertory Theatre School (1939) and at the Mask Theatre School (1940) in London. After touring with companies entertaining the troops during World War II, he joined the Birmingham Repertory Theatre and in 1946 moved to Stratford-upon-Avon, where he had his first great success—playing the title role in Henry V, Cloten in Cymbeline, Don Adriano de Armado in Love's Labour's Lost, Lucio in Measure for Measure, and Hamlet, among other Shakespearean roles. He had his first starring role in commercial theatre in 1949, playing Alexander the Great in Terence Rattigan's ill-fated Adventure Story.

Scofield had his greatest success in the role of Sir Thomas More in Robert Bolt's A Man for All Seasons, in which he appeared in London in 1960 and in New York City in 1961–62, winning the Antoinette Perry (Tony) Award (1962) and other honours. The next year he appeared at the Shakespeare Festival in Stratford, Ontario, playing in Coriolanus and Love's Labour's Lost. His later successes in the theatre included the roles of Uncle Vanya (1970) and Volpone (1977).

Scofield made his motion-picture debut in 1955, and he played More in the film version of A Man for All Seasons (1966), for which he won the Academy Award for best actor. He later played Lear in Peter Brook (Brook, Peter)'s motion-picture version of King Lear (1971) and Tobias in A Delicate Balance (1973), written by Edward Albee and directed by Tony Richardson, from the Albee play. He also played the French king in Kenneth Branagh's version of Henry V (1989) and Judge Thomas Danforth in a film adaptation of Arthur Miller's The Crucible (1996).